Moving beyond laboratory logic
Transitioning from laboratory-scale cell culture to industrial biomanufacturing is not a simple question of increasing volumes. It represents a conceptual and methodological shift in how biological systems are designed, controlled, and validated. Laboratory workflows are optimized for flexibility, rapid iteration, and experimental exploration, often tolerating variability as part of the discovery process. Industrial manufacturing, in contrast, is governed by fundamentally different constraints, where robustness, process consistency, regulatory compliance, and economic viability become central requirements.
This mismatch explains why many promising cell-based technologies demonstrate excellent performance at small scale but encounter major obstacles when industrialization is attempted. The challenge is not merely operational. It reflects a deeper misunderstanding of what scaling truly entails in biological systems.
At the center of this issue lies the distinction between scale-out and scale-up, two strategies that are frequently conflated but rely on fundamentally different principles.
Scale-out: replication without transformation
Scale-out consists of increasing production capacity by multiplying identical small-scale units. Instead of redesigning the process, the same culture vessels, protocols, and operating conditions are reproduced in parallel. This approach is attractive because it preserves familiar workflows and minimizes short-term development effort. It is therefore commonly adopted during early-stage development, pilot production, or when technical limitations prevent immediate scale-up.
However, scale-out introduces structural limitations that become increasingly pronounced as production demand grows. Replicating small units inevitably leads to:
- increased operational complexity, as multiple systems must be operated and monitored simultaneously
- expanded physical footprint, requiring more space, infrastructure, and utilities
- higher labor intensity, with increased manual handling and coordination
- greater batch-to-batch variability, even when protocols are nominally identical
As the number of parallel units increases, coordination becomes more difficult and process control remains fragmented rather than centralized. Deviations in individual units are harder to detect and correct, and overall system robustness decreases. In practice, scale-out addresses volume through duplication, not through integration, and often reaches practical limits well before industrial targets are met.
Scale-up: engineering consistency across volumes
Scale-up, in contrast, aims to increase production volume while preserving biological performance and process integrity. Rather than replicating small systems, scale-up requires redesigning the process so that cells experience equivalent conditions across different volumes. This demands a deep understanding of how cells respond to changes in physical and dynamic parameters, including mixing, mass transfer, shear stress, and spatial heterogeneity.
Unlike scale-out, scale-up forces confrontation with system-level effects. Parameters that are negligible at small scale can become dominant drivers of cell behavior at larger volumes. Flow patterns change, gradients emerge, and mechanical forces are redistributed. Successful scale-up therefore depends on technologies and strategies that ensure environmental equivalence across scales, rather than simple geometric enlargement of vessels.
This is why scale-up is inherently more challenging, but also why it is indispensable for industrial biomanufacturing.
Why scale-up is biologically non-trivial
A central insight emphasized in the biomanufacturing literature is that cells do not experience volume. Cells experience local conditions. Gradients of oxygen, nutrients, metabolites, pH, and mechanical forces define cellular fate, productivity, and stability. When these gradients change with scale, biological outcomes change accordingly, even if media composition and temperature remain constant.
At small scale, diffusion and mixing often suffice to maintain relatively homogeneous environments. At larger scales, however, transport phenomena become limiting. Oxygen transfer, nutrient distribution, and waste removal can vary significantly within the same vessel. These local variations introduce heterogeneity, leading to differences in growth rate, metabolism, and product quality.
This explains why laboratory protocols frequently fail when transferred directly to industrial systems. Without deliberate control of physical and dynamic parameters, scale-up introduces unintended stress, altered cellular states, and loss of reproducibility. Scale-up must therefore be understood as a biophysical and systems-engineering challenge, not merely a logistical one.
Designing processes for industrial reality
Industrial biomanufacturing requires platforms and processes that are conceived with scale-up in mind from the outset, rather than adapted retrospectively. This implies prioritizing design principles that support robustness and reproducibility at large scale.
Key requirements include:
- predictable control of shear and mixing, avoiding damaging mechanical extremes
- homogeneous mass transfer throughout the culture volume
- reproducible operating conditions across scales and batches
- simplified process validation and technology transfer
Processes optimized exclusively for small-scale convenience often encounter hard limits during industrialization, necessitating costly redevelopment cycles. In contrast, scale-aware process design enables smoother transitions from research and development to production, reducing both technical risk and time to market.
From experimental success to industrial reliability
The distinction between scale-out and scale-up reflects a broader truth. Industrial biomanufacturing is not an extension of the laboratory, but a fundamentally different operating paradigm. Experimental success at small scale does not guarantee industrial viability unless scale-dependent effects are explicitly addressed.
Achieving reliable, cost-effective cell production requires aligning biological requirements with engineering constraints from the earliest stages of development. This alignment transforms scaling from a reactive challenge into a design principle, enabling the translation of promising cell-based technologies into manufacturable products capable of meeting real-world demand.
